Adenosine deaminase-deficient severe combined immunodeficiency (ADA-SCID) is a severe rare primary immunodeficiency characterized by impaired T-, B-, and NK-cell development and accounts for 10-15% of all cases of SCID (Hershfield et al. 1998). Typically, ADA-SCID is an autosomal recessive monogenic metabolic condition that causes immunodeficiency. It is caused by deficiency in the enzyme adenosine deaminase (ADA). The enzyme (ADA) catalyses the deamination of deoxyadenosine and adenosine to deoxyinosine and inosine respectively, and the lack of normal levels of ADA leads to increased intracellular conversion of deoxyadenosine to deoxyadenosine triphosphate (dATP) thus expanding the dATP pool. High levels of dATP affect lymphocyte development, viability, and function causing the immune defects seen in this condition (Apasov et al. 2001).
Clinically, patients present with failure to thrive, recurrent and opportunistic infections and death in the first year of life if left untreated (Albuquerque and Gaspar 2004; Ratech et al. 1985). A murine model recapitulates the human disease with similar metabolic and immunological abnormalities and untreated mice die after 3 weeks from pulmonary insufficiency, which results from the metabolic consequences of the disease (Blackburn et al. 1998).
Treatment options for ADA-SCID are limited and the mainstay of treatment is allogeneic hematopoietic stem cell transplant (HSCT). However, survival following HSCT from matched unrelated donors (67%), mismatched unrelated donors (29%), or parental donors (43%) is poor (Booth et al. 2006). Enzyme replacement therapy (ERT) with pegylated bovine ADA (PEG-ADA) results in metabolic detoxification, but long-term immune recovery is suboptimal and very poor in some cases (Gaspar et al. 2009). A further limitation to PEG-ADA therapy is the cost. As an orphan drug, the cost is high and treatment of a small child may cost between £150,000 to £300,000 per year. With increase in age and size, these costs will increase, since ADA therapy is palliative and not curative, treatment must be continued throughout the life of the patient. Thus, there is a clear need for effective and sustained alternative treatment options.
Early trials of GT using γ-retroviral vectors (gRVs) targeting correction of peripheral blood (PB) lymphocytes or autologous hematopoietic stem cells (HSCs) or a combination of the two showed only limited success, and any observed immune recovery could not be attributed to the GT, since ERT was continued after the GT procedure (Blaese et al. 1995). Indeed, in the three studies so far undertaken, immune reconstitution remains suboptimal with T-cell numbers at the lower limit of the normal range and approximately half of the patients remaining on immunoglobulin replacement therapy due to incomplete B-cell reconstitution (Aiuti et al. 2009; Candotti et al. 2012; Gaspar et al. 2011).
Further, the ongoing use of gRVs has raised concerns, as GT for monogenic diseases has often been complicated by the development of adverse effects. In clinical trials of gRV-mediated autologous HSC GT for SCID-X1, X-CGD and Wiskott-Aldrich syndrome, there has been a high incidence of gRV-mediated insertional mutagenesis (Bortug et al. 2010; Hacein-Bey-Abina et al. 2008; Hacein-Bey-Abina et al. 2003; Howe et al. 2008; Ott et al. 2006; Stein et al. 2010). Upon vector integration, the strong enhancer elements that reside in the long terminal repeat (LTR) promoter elements of gRVs can transactivate adjacent genes to initiate the transformation process. In ADA gRV studies, vector insertions near known oncogenes have also been reported (Aiuti et al. 2007).
Thus, although HSCT and ERT are used clinically to try and manage the progression of ADA-SCID, and trials with gRVs have taken place, effectiveness of these treatment options is limited by the availability of suitable donor tissue, adverse immune responses such as Graft versus Host Disease (GvHD), poor efficacy such as poor gene marking and/or poor immune recovery, and/or safety concerns.